Last year, the MGFA dedicated $1 million to research activities, including grants to exceptional scientific minds who are pioneering research in myasthenia gravis and related neuromuscular disorders.
One of those is Aimee Payne, MD, PhD, a specialist in rare autoimmune skin disease.
She received the inaugural Nancy Law Impact Award in 2022 to support her research exploring a precision medicine approach to MG.
A professor of dermatology at the University of Pennsylvania, Dr. Payne is evaluating how to target MuSK autoantibody-producing B-cells while preserving healthy B-cells. This work could potentially help patients with MuSK MG find significant relief from their symptoms – perhaps even cause remission – without depleting their immune system.
Dr. Payne talked to MGFA about her background, her work with CAAR-T cell therapies, and why she’s excited about this prospective treatment for myasthenia gravis.
Q: How and why did you get into scientific and medical research?
I became interested in medical research when I was in college at Stanford University. My mentor back then, Gilbert Chu, studied rare genetic syndromes where you can’t repair your DNA after it’s damaged by sunlight. Those patients end up getting severe sun sensitivity and skin cancers at an early age. So that got me hooked on how the basic science of DNA repair can mesh with the clinical care of patients.
I ended up applying to MD/PhD programs after college to learn how to become a physician scientist. I ultimately became a dermatologist who studies rare autoimmune skin diseases, specifically pemphigus, where your body mistakenly makes antibodies that attack your skin cells, causing them to fall apart and blister.
Q: How did you end up working on myasthenia gravis?
We developed a targeted therapy for pemphigus and then began to think how we could apply that to other, similar antibody-mediated diseases. Myasthenia gravis really jumped to the top because it’s one of the best characterized autoimmune diseases, based on decades of work by people affiliated with the MGFA – basic researchers, translational researchers, clinical researchers – aiming to better understand how autoimmunity occurs in MG.
There are really a lot of parallels between pemphigus and myasthenia gravis, particularly the MuSK subset, and that’s what got us focusing on MuSK MG. We started collaborating with people in the community to develop a targeted therapy for MuSK MG.
Q: Your research has focused on using CAAR-T cells to target the B-cells that produce anti-MuSK autoantibodies. Tell us about your approach.
We have invented a precision-medicine approach for antigen-specific B-cell depletion in MuSK myasthenia gravis that we call chimeric autoantibody receptor therapy, or CAAR-T. Anti-C19 chimeric antigen receptor (CAR)-T is FDA-approved for the treatment of B-cell leukemia and lymphoma, and that approach is very effective for cancers. It also leaves a patient potentially immunosuppressed for the rest of their lives; some of them have to get lifelong IVIG infusions to maintain normal immunity. But the remarkable nature of the cures that were induced by that therapy got our attention.
So, the idea was, instead of wiping out all of your B-cells, could we just eliminate immune cells that are expressing anti-MuSK autoantibodies?
We have taken several key steps to move research forward. We showed proof of concept in mice, which were given an experimental form of myasthenia gravis in which we induced an antibody response, and published those results in Nature Biotechnology in January 2023.
We collaborated with other researchers, such as Kevin O’Connor at Yale, to engineer target cells in the laboratory to express human B-cell receptors that target MuSK and see if we could kill them. We also ended up collaborating with MuSK MG physicians to give us blood samples containing anti-MuSK B-cells from these patients to see if these CAAR-T cells could kill them in a dish. And then we worked with several clinicians and researchers in the field to help us design the clinical trial protocol.
Based on that, we were able to launch the Phase 1 study, which received FDA clearance for the investigational new drug application in 2022. We’re bringing on new sites by the month. Right now we’re working with sites at UC Irvine, UC Davis, University of Kansas, and University of Oregon.
Q: How does this potential treatment approach benefit patients?
Pemphigus used to be fatal. Before steroids, you could actually blister off all of your skin and mucous membranes. You couldn’t eat. You were like a burn patient in the hospital. It was a terrible outcome.
Now that steroids and rituximab are available, patients are no longer dying from their disease, but they are potentially suffering from the immunosuppression caused by the therapies that I prescribe to control the disease.
If you talk to physicians who treat pemphigus or MG, one of the concerns is that most therapies suppress your immune system broadly. This was really highlighted during the pandemic, when rituximab was associated with a four to five-fold higher risk of hospitalization or death from COVID-19 just because it impaired the immune system. So that was the problem we were trying to solve from the patient and the physician perspective.
For me, precision medicine has always been the holy grail of what we’re trying to achieve. With a precision approach, we’re leaving most of your B-cells alone and just targeting less than 1% of your normal B-cell population.
And one powerful advantage of engineered cells is they have the potential to persist for a lifetime after infusion – or at least months to years. The hope with CAAR-T cell therapy is that, if it is effective at achieving this MuSK-specific B-cell depletion, we could safely put disease in remission after a single infusion.
Q: What excites you about being an autoimmune disease researcher today?
MG is a super exciting space. There’s a broad range of therapies that are advancing to clinical trials.
The diversity is great for a number of reasons. Obviously, we hope that will bring better therapies to patients, but also, from a biological perspective, we’re learning a lot about the biological pathways of MG. The ultimate goal is not to make patients a little bit better – we really want to cause long-term remission of disease.
Q: What does it mean to you to be a MGFA grant recipient?
Organizations like MGFA are so critical because you’re increasing the awareness of MG. Tens of millions of people in the country have diabetes, but only tens of thousands have myasthenia gravis and people may have never heard of the disease.
In study sections when funders are considering grant applications, you might hear, “That’s such a rare disease, MuSK myasthenia gravis – why don’t we fund studies that are going to affect millions of people? Won’t we get more bang for our buck?” That’s why it is so helpful for patient organizations to support research funding in these rare disease fields.
I’m really so honored that MGFA recognized the connection between our work with pemphigus and how it applies to myasthenia gravis. It’s invaluable because I don’t think that this kind of research is typically supported by traditional grant-funding mechanisms.